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The serine hydrolase ABHD6 controls survival and thermally induced seizures in a mouse model of Dravet syndrome

Evidence suggests that inhibition of α/β hydrolase-domain containing 6 (ABHD6) reduces seizures; however, the molecular mechanism of this therapeutic response remains unknown. We discovered that heterozygous expression of Abhd6 (Abhd6(+/−)) significantly reduced the premature lethality of Scn1a(+/−)...

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Autores principales: Westenbroek, Ruth, Kaplan, Joshua, Viray, Katie, Stella, Nephi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10332637/
https://www.ncbi.nlm.nih.gov/pubmed/36990366
http://dx.doi.org/10.1016/j.nbd.2023.106099
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author Westenbroek, Ruth
Kaplan, Joshua
Viray, Katie
Stella, Nephi
author_facet Westenbroek, Ruth
Kaplan, Joshua
Viray, Katie
Stella, Nephi
author_sort Westenbroek, Ruth
collection PubMed
description Evidence suggests that inhibition of α/β hydrolase-domain containing 6 (ABHD6) reduces seizures; however, the molecular mechanism of this therapeutic response remains unknown. We discovered that heterozygous expression of Abhd6 (Abhd6(+/−)) significantly reduced the premature lethality of Scn1a(+/−) mouse pups, a genetic mouse model of Dravet Syndrome (DS). Both Abhd6(+/−) mutation and pharmacological inhibition of ABHD6 reduced the duration and incidence of thermally induced seizures in Scn1a(+/−) pups. Mechanistically, the in vivo anti-seizure response resulting from ABHD6 inhibition is mediated by potentiation of gamma-aminobutyric acid receptors Type-A (GABA(A)R). Brain slice electrophysiology showed that blocking ABHD6 potentiates extrasynaptic (tonic) GABA(A)R currents that reduce dentate granule cell excitatory output without affecting synaptic (phasic) GABA(A)R currents. Our results unravel an unexpected mechanistic link between ABHD6 activity and extrasynaptic GABA(A)R currents that controls hippocampal hyperexcitability in a genetic mouse model of DS. BRIEF SUMMARY: This study provides the first evidence for a mechanistic link between ABHD6 activity and the control of extrasynaptic GABA(A)R currents that controls hippocampal hyperexcitability in a genetic mouse model of Dravet Syndrome and can be targeted to dampened seizures.
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spelling pubmed-103326372023-07-10 The serine hydrolase ABHD6 controls survival and thermally induced seizures in a mouse model of Dravet syndrome Westenbroek, Ruth Kaplan, Joshua Viray, Katie Stella, Nephi Neurobiol Dis Article Evidence suggests that inhibition of α/β hydrolase-domain containing 6 (ABHD6) reduces seizures; however, the molecular mechanism of this therapeutic response remains unknown. We discovered that heterozygous expression of Abhd6 (Abhd6(+/−)) significantly reduced the premature lethality of Scn1a(+/−) mouse pups, a genetic mouse model of Dravet Syndrome (DS). Both Abhd6(+/−) mutation and pharmacological inhibition of ABHD6 reduced the duration and incidence of thermally induced seizures in Scn1a(+/−) pups. Mechanistically, the in vivo anti-seizure response resulting from ABHD6 inhibition is mediated by potentiation of gamma-aminobutyric acid receptors Type-A (GABA(A)R). Brain slice electrophysiology showed that blocking ABHD6 potentiates extrasynaptic (tonic) GABA(A)R currents that reduce dentate granule cell excitatory output without affecting synaptic (phasic) GABA(A)R currents. Our results unravel an unexpected mechanistic link between ABHD6 activity and extrasynaptic GABA(A)R currents that controls hippocampal hyperexcitability in a genetic mouse model of DS. BRIEF SUMMARY: This study provides the first evidence for a mechanistic link between ABHD6 activity and the control of extrasynaptic GABA(A)R currents that controls hippocampal hyperexcitability in a genetic mouse model of Dravet Syndrome and can be targeted to dampened seizures. 2023-05 2023-03-27 /pmc/articles/PMC10332637/ /pubmed/36990366 http://dx.doi.org/10.1016/j.nbd.2023.106099 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ).
spellingShingle Article
Westenbroek, Ruth
Kaplan, Joshua
Viray, Katie
Stella, Nephi
The serine hydrolase ABHD6 controls survival and thermally induced seizures in a mouse model of Dravet syndrome
title The serine hydrolase ABHD6 controls survival and thermally induced seizures in a mouse model of Dravet syndrome
title_full The serine hydrolase ABHD6 controls survival and thermally induced seizures in a mouse model of Dravet syndrome
title_fullStr The serine hydrolase ABHD6 controls survival and thermally induced seizures in a mouse model of Dravet syndrome
title_full_unstemmed The serine hydrolase ABHD6 controls survival and thermally induced seizures in a mouse model of Dravet syndrome
title_short The serine hydrolase ABHD6 controls survival and thermally induced seizures in a mouse model of Dravet syndrome
title_sort serine hydrolase abhd6 controls survival and thermally induced seizures in a mouse model of dravet syndrome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10332637/
https://www.ncbi.nlm.nih.gov/pubmed/36990366
http://dx.doi.org/10.1016/j.nbd.2023.106099
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